Genital herpes and human immunodeficiency virus: double trouble

447-453 03-002568.indd447Bulletin of the World Health Organization | June 2004, 82 (6)
Abstract The synergistic relationship between herpes simplex virus type 2 (HSV-2) and transmission of human immunodeficiency virus (HIV) can be substantial in developing countries that have high prevalences of both viral infections. Genital herpes, most frequently caused by HSV-2, has become the leading cause of genital ulcer disease worldwide. This review of recent research on genital herpes and enhanced susceptibility to, and transmission of, HIV is part of the “Advances in HIV/AIDS research series” which endeavours to form a bridge between the research into HIV and acquired immunodeficiency syndrome (AIDS) and the practice of HIV/AIDS prevention, care and support in developing countries. Research findings have shown that being seropositive for HSV-2 can increase the risk of HIV acquisition among high-risk HIV-negative people exposed to HIV and, likewise, the infectiousness of individuals co-infected with HIV-1 and HSV-2 can increase during periods of HSV-2 reactivation. These observations have led to the initiation of several intervention trials and could ultimately lead to the setting of new priorities in public health and clinical practice. WHO has recently issued new guidelines for the syndromic management of genital ulcer disease that include antiviral treatment for lesions consistent with genital herpes. The United States Centers for Disease Control and Prevention issued updated Sexually Transmitted Diseases Treatment Guidelines in 2002 that recommended the use of type-specific serological tests for diagnosing HSV-2. Recently launched proof-of-concept, HSV-2 intervention trials in several countries will help to determine the proportion of new HIV infections that could be prevented by suppression of HSV-2, and the findings from these studies will inform those involved in setting prevention and treatment priorities and strategies in developing countries.
Keywords Herpes genitalis/epidemiology/diagnosis/therapy; HIV infections/transmission; Acquired immunodeficiency syndrome/etiology; Herpesvirus 2, Human/pathogenicity; HIV-1/pathogenicity; Comorbidity; Disease susceptibility; Review literature (source: MeSH, NLM). Mots clés Herpès génital/épidémiologie/diagnostic/thérapeutique; HIV, Infection/transmission; SIDA/étiologie; Herpèsvirus 2 humain/ pathogénicité; VIH-1/pathogénicité; Morbidité associée; Sensibilité à maladie; Revue de la littérature (source: MeSH, INSERM). Palabras clave Herpes genital/epidemiología/diagnóstico/terapia; Infecciones por VIH/transmisión; Síndrome de inmunodeficiencia adquirida/etiología; Herpesvirus 2 humano/patogenicidad; VIH-1/patogenicidad; Comorbilidad; Susceptibilidad a enfermedades; Literatura de revisión (fuente: DeCS, BIREME).
Bulletin of the World Health Organization 2004;82:447-453.
Voir page 451 le résumé en français. En la página 451 figura un resumen en español.
Genital herpes and human immunodeficiency virus: double trouble Connie Celum,1 Ruth Levine,2 Marcia Weaver,3 & Anna Wald1
1 Division of Allergy and Infectious Diseases, Department of Medicine and Department of Epidemiology, University of Washington, Seattle, WA, USA. 2 Center for Health Education and Research, University of Washington, Seattle, WA, USA. 3 Department of Health Services, University of Washington, 901 Boren Avenue, Suite 900, Seattle, WA 98104, USA (email: [email protected]). Correspondence should be sent to this author. Ref. No. 03-002568 (Submitted: 14 February 2003 – Final revised version received: 29 August 2003 – Accepted: 17 September 2003)
Introduction Herpes simplex virus type 2 (HSV-2), is a sexually transmit- ted infection (STI) that is chronic, widespread, and infectious during both its symptomatic and asymptomatic periods. This infection is a significant factor for increased risk of acquisi- tion and transmission of HIV. A meta-analysis of studies on HSV-2 found that infection with HSV-2 doubled the risk of becoming infected with HIV through transmission during sexual activity (1). Furthermore, HSV-2 is the leading cause of genital ulcer disease worldwide. New prevention strategies are urgently needed to reduce the contribution of HSV-2 to HIV transmission, particularly in developing countries that have high prevalence of both HSV-2 and HIV.
The existence of a synergistic relationship between HSV-2 and transmission of HIV has been indicated by many observational and biological studies in which HSV-2 has been implicated as a cofactor in the acquisition and transmission of HIV. HSV-2 causes ulcers and micro-ulcerations, which are often asymptomatic and thus unrecognized; these breaks in the mucosa and the skin in the genital area create portals for the entry of HIV. HSV-2 lesions contain substantial numbers of CD4+ lymphocytes, which are target cells for HIV. Laboratory studies have shown that these CD4+ lymphocytes are likely to facilitate the acquisition of HIV in HIV-negative, HSV-2- positive individuals when they are exposed to HIV. Episodes of reactivation of HSV-2 are associated with increased shedding of HIV from lesions and genital mucosa.
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Policy and Practice Genital herpes and human immunodeficiency virus Connie Celum et al.
Researchers who have conducted epidemiological and clinical studies on HSV and HIV have proposed that inter- ventions that target HSV-2 infection would provide a way to intervene in transmission of both HIV and HSV-2. Until very recently, most sexually transmitted disease (STD) interventions have focused on bacterial STIs, which are easier to diagnose and treat than genital herpes. As a result, little attention has been paid to the diagnosis of genital herpes and there has been a lack of prevention interventions; consequently, the epidemics of HSV-2 and HIV continue to fuel each other. In some parts of sub-Saharan Africa, where HIV is of great concern, the prevalence of HSV-2 among women is as high as 75% (2).
Recently, large-scale, proof-of-concept, intervention trials have been launched at several sites to determine whether suscep- tibility to and infectiousness of HIV can be reduced either by treating HSV-2 episodically or by suppressing HSV-2 reactiva- tion. Although there is no cure for genital herpes, the drugs acyclovir, valacyclovir and famciclovir can shorten initial or recurrent episodes (“episodic” therapy). These drugs may also be taken daily for suppression of herpes, which dramatically reduces the frequency and severity of recurrences of HSV-2 (“suppressive” therapy). Support for the concept that antiviral suppression can interrupt transmission of HSV-2 was provided by the results of a recent multi-country, randomized, double- blind study by Corey et al. who found that suppressive therapy with valacyclovir reduced transmission of HSV-2 by 50% for both men and women in heterosexual HSV-2-discordant couples (3).
It is not yet clear which strategy for the diagnosis and management of HSV-2 will be the most feasible and effective in developing countries. The options range from widespread screening for HSV-2 and suppressive antiviral therapy, to other strategies that may have benefits in reducing HSV-2 transmission as well as in HIV prevention. Studies currently being conducted will provide more data on which policy-makers can base their decisions as to the most feasible and cost-effective approaches. Additionally, WHO has incorporated empirical treatment for HSV-2 into its management recommendations for the syn- dromic management of genital ulcer disease (4). The impetus for such a significant change in treatment approaches has come from the accumulation of recent research findings and the high prevalence of HSV-2 in many countries.
Methods This paper provides an overview of the research on HSV-2 and HIV published since 2000. We (CC and AW) identified articles, reports and abstracts published during or after 2000. An online MEDLINE search for articles published in English during or after 2000 was also conducted.
Current state of research The relationship of HSV-2 to acquisition and transmission of HIV The majority of epidemiological studies have assessed the role of HSV-2 in increasing the risk of HIV acquisition, because of the difficulty of conducting studies of sexual transmission of HIV. Substantial biological data from in vivo and in vitro studies support the hypothesis that HSV-2 increases HIV infectiousness.
Genital herpes and enhanced susceptibility to HIV In a meta-analysis of the epidemiological literature related to HSV-2 and the risk of HIV infection, Wald & Link (1) found that people infected with HSV-2 had a risk of becoming in- fected with HIV twice as high as that in those who were not infected with HSV-2. The meta-analysis was based on the most rigorous studies that documented HSV-2 infection that had occurred prior to infection with HIV.
Rodríguez et al. conducted a nested case–control study in the Mwanza region of the United Republic of Tanzania to explore the relationship and time sequence between prevalent and incident HSV-2 infection and HIV seroconversion among 127 men and women (5). They discovered a strong association between HSV-2 status and HIV seroconversion among the 70 male study subjects, and reported that 60 of these HIV serocon- versions occurred in men with HSV-2 infection. The adjusted odds ratio for HIV incidence in HSV-2-positive men was higher for the male subjects who seroconverted to HSV-2 during the 2-year follow-up period than for those who were HSV-2-seroposi- tive at baseline, suggesting that the severity and more frequent reactivation of new HSV-2 infections plays an important role in increasing the risk of HIV acquisition. The findings from female study subjects were not statistically significant.
In a cross-sectional study of 1507 subjects aged 14–24 years in the mining district of Carletonville, South Africa, Auvert et al. determined that HSV-2 seropositivity was a risk factor for HIV infection (6). Nine per cent of the young men and 34% of the young women in the study area were infected with HIV, and HSV-2 seroprevalence was almost twice as high (17% among men and 53% among women). HSV-2 seropositivity was strongly associated with HIV infection: men who were seropositive for HSV-2 were seven times more likely to be HIV-positive than men who were seronegative for HSV-2. Among the individuals infected with HIV, 91% of the women and 65% of the men were co-infected with HSV-2.
Buvé et al. (7) explored the factors that influence the differences in HIV prevalence in four cities in Africa, two with a high prevalence of HIV: Kasumi, Kenya, and Ndola, Zambia, and two in which the prevalence of HIV is relatively low: Cotonou, Benin, and Yaoundé, Cameroon. They reported that higher prevalences of HSV-2 in men and women, and of trichomoniasis in women and the lower prevalence of circumci- sion of males in the two cities that had a high prevalence of HIV played a greater role than sexual behaviour in explaining the differences in HIV prevalence between the four cities studied. Given the high HSV-2 seroprevalence in Kisumu and Ndola, Buvé and colleagues hypothesized that as the prevalence of HIV and HSV-2 increased in these cities, the two viruses fuelled transmission of one another by increasing susceptibility and infectiousness. Weiss et al. (8) looked more specifically at the role of HSV-2 in this study and found that in three of the four cities studied by Buvé et al., the prevalence rates of HSV-2 were higher than 50% in women and 25% in men. In all four cities, the prevalences of HSV-2 and HIV were strongly correlated.
Genital herpes and enhanced transmission of HIV In a prospective study of 12 HSV-2-seropositive, HIV-positive men, Schacker et al. (9), detected HIV-1 RNA in lesions in 25 out of 26 episodes (i.e. periodic reactivations) of genital herpes, with a modestly higher quantity of HIV in genital lesions than in blood, suggesting that HSV reactivation could increase infec- tiousness of HIV in people co-infected with HIV and HSV.
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Policy and Practice Connie Celum et al. Genital herpes and human immunodeficiency virus
In the Rakai community-randomized trial of mass STD treatment, researchers looked at factors that increased the risk of HIV transmission in HIV-discordant, monogamous couples, including HSV-2 serostatus, HIV viral load in the HIV-posi- tive partner and sexual activity. Gray et al. (10) estimated the probability of HIV-1 transmission per sex act by studying 174 monogamous HIV-discordant couples identified retrospectively, among whom 38 of the HIV-negative partners seroconverted to HIV-positive. Recent genital ulcers and higher levels of HIV in blood significantly increased the likelihood of transmission of HIV in these HIV-discordant couples (10, 11). Gray et al. (10) found that the probability of transmission of HIV-1 was approximately four times higher for those study subjects with genital ulcers than for those without.
The prevalence of HSV-2 is one factor that may explain the different outcomes in the STD intervention trials conducted in Mwanza, the United Republic of Tanzania, Masaka, Uganda and Rakai, Uganda. Three rounds of mass treatment for bacterial STIs were given every 10 months in 56 communities in the rural Rakai district of Uganda from 1994 to 1997. The intervention trial resulted in a modest decrease in the prevalence of syphilis but no reduction in the incidence of HIV-1 (12). In the same setting, HSV-2 was identified as the cause of 45% of the genital ulcers that were tested and that had a confirmed etiology (12). Also, the HIV-1 epidemic in the Rakai district was at a mature stage, with a much higher prevalence of HIV-1 and a higher incidence of HIV-1 than that in the Mwanza region in the United Republic of Tanzania, where strengthened syndromic management of STDs reduced HIV incidence by 40% (12). In mature epidemics, a larger proportion of the population is infected with HIV-1. People who are co-infected with HIV and HSV-2 may experience more frequent episodes of genital herpes with symptomatic lesions and ulcers than people who are HIV-negative, which may also increase their risk of transmit- ting HIV-1 to others. Kamali et al. (13) found that behavioural interventions and improved syndromic management of STI had little effect on the incidence of HIV-1 in the Masaka district of Uganda, a region where there is a mature HIV-1 epidemic and a significant prevalence of HSV-2.
To assess the outcomes of these three STI intervention trials that focused on different strategies to control bacterial STDs, Orroth and colleagues compared sexual behaviours and STD prevalence in the three populations studied and determined that in subjects aged 15–29 years, the adjusted prevalence of HSV-2 in Rakai was 43% in women and 21% in men; in Mwanza, 47% in women and 13% in men; and in Masaka, 44% in women and 17% in men (14). The high prevalence of HSV-2 in all three sites of these community-randomized STD intervention trials indicates that genital herpes may be an important factor in explaining the different outcomes of the trials. Infection with HSV-2 was much more prevalent than all other bacterial STDs combined. This underscores the need for further trials to characterize the relationship that exists between HSV-2 and HIV transmission and to identify effec- tive interventions.
Shedding of HSV-2 in asymptomatic people and risk of transmission In the 1990s more sensitive diagnostic tests, such as the poly- merase chain reaction (PCR) assay, allowed researchers to better characterize the pattern and frequency with which asymptomatic people infected with HSV-2 shed virus; at such times asymp- tomatically infected individuals could unknowingly transmit
HSV-2 to their sexual partners. Wald et al. (15) measured the frequency of HSV shedding in HSV-2-seropositive women using both the sensitive HSV PCR assay and the standard viral isolation culture method. In this study, the HSV-2 detection rate using the PCR assay was 3.5 times higher than that using the culture method; viral shedding was detected on 28% of the days tested. Wald et al. (16) compared genital shedding in 53 HSV-2-seropositive subjects who had no history of genital herpes with that in 90 HSV-2-seropositive subjects who had symptomatic disease. Interestingly, after patient education about genital herpes, 46 of the 53 asymptomatic persons did report lesions or other symptoms. The rate of subclinical shedding was similar in both groups, consistent with infection with genital herpes. HSV-2 was detected in the genital secretions of 44 of the 53 individuals in the group of HSV-2 seropositive subjects who did not report a history of genital herpes. In general, the recurrent episodes in these subjects were shorter and less frequent than those reported in the group of 90 patients with known symptomatic disease. Krone et al. (17) studied the frequency of viral shedding in HSV-2-seropositive, HIV-negative men who had sex with men, and found that shedding of HSV occurred on 5.5% of the days on which cultures were obtained. Shedding of HSV-2 was found to occur primarily in the anal and rectal region, and on almost half of the days on which HSV-2 was detected, no lesions were present.
The frequency of viral shedding has substantial implica- tions for counselling patients about the natural history and risk of transmission of HSV-2 even when no lesions are recognized (i.e. subclinical shedding).
Diagnosis and treatment of HSV-2 New type-specific serological assays and PCR have dramatically improved the ability to identify and diagnose HSV-2, and have increased the feasibility of large-scale HSV-2 vaccine trials and of HSV-2 intervention trials. As yet there are not enough data available to establish which diagnostic and treatment strategies, whether alone or in combination, will prove effective in reducing the prevalence of HSV-2 in developing countries. To date HSV-2 vaccine trials have not demonstrated substantial efficacy. HSV-2 intervention trials exploring episodic and suppressive therapy with acyclovir in developing countries are just beginning and will raise as many questions as they answer about the feasibility and implementation of programmes in countries with varying resources. New WHO guidelines for the syndromic manage- ment of genital ulcer disease are likely to result in more people being diagnosed with and treated for HSV-2, although the overall impact on prevalence of HSV-2 and on HSV-2 and HIV transmission will not be evident for several years (4).
Testing for herpes simplex virus Serological screening for genital herpes will be an essential “cor- nerstone” of prevention strategies as most people infected with HSV-2 are unaware of their infection. For the minority of people who present with genital lesions, clinical diagnosis is unreliable because of the diverse and subtle symptoms of HSV-2 infection. Herpes ulcers often mimic other causes of genital ulcers, such as chancroid, another STI, and may be misdiagnosed even by experienced clinicians (18).
Type-specific serological assays, which were developed in the 1990s and are now commercially available, enable the detection of HSV-2 in asymptomatic individuals. Before these tests became available, no commercially available HSV antibody
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Policy and Practice Genital herpes and human immunodeficiency virus Connie Celum et al.
tests were able to differentiate between infection with HSV-1 (a related herpesvirus, most commonly associated with cold sores on the mouth) and HSV-2. These new assays have acceptably high sensitivity and specificity for use in many settings, particu- larly in those with a high prevalence of infection (18). The HSV Western blot differentiates between antibodies to HSV-1 and HSV-2 and was developed more than a decade ago at the University of Washington, USA, but is not commercially avail- able. Although regarded as the gold standard for such tests, its high cost (US$ 95), the technical skill and experience required to conduct it, and the time needed for its performance prohibit its widespread use in developing countries (18). All serological assays have a time lag before antibodies are detectable after initial acquisition of HSV-2, the duration of which can range from several weeks up to several months (18).
Vaccines against HSV-2 A recombinant subunit vaccine to prevent the acquisition of HSV-2 has been tested in clinical trials. The vaccine showed sig- nificant efficacy in reducing symptomatic genital herpes among women who did not also have HSV-1 antibodies, but very little efficacy in protecting women from HSV-2 infection (19). This vaccine is undergoing further evaluation and other candidate HSV-2 vaccines are at earlier stages of testing.
Syndromic management of HSV-2 WHO has incorporated empirical antiviral treatment for HSV-2 into the syndromic management of genital ulcer disease based on clinical appearance (vesicles or ulcers), history of recur- rent lesions and prevalence of HSV-2 in the population (4). Traditionally, syndromic management has focused attention on chancroid and syphilis, two bacterial STIs that also cause genital ulcer disease, but that have declined in prevalence over the past decade. In areas such as sub-Saharan Africa, where the prevalence of HSV-2 is high, such…